Molecular mechanism of drug-drug interactions and drug-P450 family enzyme interactions are very important for understanding drug metabolism and toxicity, and also guiding drug discovery. The first step for drug-drug interactions and drug-enzyme interactions before their metabolization is the process of drug binding to the metabolism enzyme. This process involves multi-drug binding[1]. Many computational studies have been done to discover different drugs binding to the enzymes but with only one drug molecule involved in the simulation[2, 3]. As lots of experiments have shown that several same and/or different types of drug molecules could bind to the enzyme simultaneously[4, 5]. How does this process happen at atomistic level? Is there time sequencing for different drug molecules binding or not? What is the dynamics behavior of enzyme upon multi-drug binding? Is it different for the enzyme to bind single drug and multi-drug molecules? To uncover these questions, we will adapt two strategies. Firstly, simulated annealing techniques will be used to find the possible initial binding complex structures, and then molecular dynamics will be adapted to relax and finely tune the relative position and orientation of these drug molecules in the binding pocket of enzyme. This two-step modeling procedure will be done many thousands times to find \"good\" binding pose; Second strategy is that multi-copy of drug molecules are included in the molecular dynamics simulation, but the interaction between drug molecules are not calculated at first step, only the interaction involving drug-enzyme and enzyme itself will be computed, at second step the final pose from 1st step will be submitted to the normal molecular dynamics simulation with all the interaction included. Several marketed drugs[6] and p450-3A4 will be selected and tested.; Molecular mechanism of drug-drug interactions and drug-P450 family enzyme interactions are very important for understanding drug metabolism and toxicity, and also guiding drug discovery. The first step for drug-drug interactions and drug-enzyme interactions before their metabolization is the process of drug binding to the metabolism enzyme. This process involves multi-drug binding[1]. Many computational studies have been done to discover different drugs binding to the enzymes but with only one drug molecule involved in the simulation[2, 3]. As lots of experiments have shown that several same and/or different types of drug molecules could bind to the enzyme simultaneously[4, 5]. How does this process happen at atomistic level? Is there time sequencing for different drug molecules binding or not? What is the dynamics behavior of enzyme upon multi-drug binding? Is it different for the enzyme to bind single drug and multi-drug molecules? To uncover these questions, we will adapt two strategies. Firstly, simulated annealing techniques will be used to find the possible initial binding complex structures, and then molecular dynamics will be adapted to relax and finely tune the relative position and orientation of these drug molecules in the binding pocket of enzyme. This two-step modeling procedure will be done many thousands times to find \"good\" binding pose; Second strategy is that multi-copy of drug molecules are included in the molecular dynamics simulation, but the interaction between drug molecules are not calculated at first step, only the interaction involving drug-enzyme and enzyme itself will be computed, at second step the final pose from 1st step will be submitted to the normal molecular dynamics simulation with all the interaction included. Several marketed drugs[6] and p450-3A4 will be selected and tested.